(a) Field of the Invention
This invention relates to pharmaceutical compositions containing a class of 2-(4-substituted)phenylmethylene derivatives useful as inhibitors of 5-lipoxygenase, an enzyme which plays an important role in leukotriene biosynthesis. This invention also relates to the use of 5-phenyl-1,3-dioxoalkenyl compounds as inhibitors of 5-lipoxygenase. By inhibiting 5-lipoxygenase and thus leukotriene biosynthesis, the compounds of this invention are useful in preventing or alleviating conditions associated with leukotrienes, such as allergic reactions, inflammatory conditions, immediate hypersensitivity reactions, asthma, and certain proliferative skin disorders such as psoriasis.
Arachidonic acid is converted enzymatically to various biologically active products, such as prostaglandins, thromboxanes, various hydroxyeicosatetraenoic and hydroperoxyeicosatetraenoic acids, and leukotrienes. The leukotrienes, products of the 5-lipoxygenase pathway, are implicated in allergic reactions, particularly asthma, see M. Griffin et al. , N. Engl. J. Med. , 308 , 436-439 (1983); inflammatory conditions; and skin diseases such as psoriasis. One leukotriene, LTD.sub.4, is the major active constituent of slow reacting substance of anaphylaxis (SRS-A), a potent bronchoconstrictor that is released during allergic reactions. See R. A. Lewis and K. F. Austen, Nature , 293 , 103-108 (1981). When administered to humans and guinea pigs, LTD.sub.4 causes bronchoconstriction by two mechanisms: 1) directly by stimulating smooth muscle; and 2) indirectly through release of thromboxane A.sub.2, which causes contraction of respiratory smooth muscle. Because antihistamines are ineffective in the management of asthma, SRS-A is believed to be a mediator of the bronchoconstriction occurring during an allergic attack. LTD.sub.4 may also be involved in other inflammatory conditions such as rheumatoid arthritis. Another leukotriene, LTC.sub.4, is also a very potent bronchoconstrictor. A third leukotriene, LTB.sub.4, is associated with leukocyte chemotaxis, a phenomenon in which leukocytes migrate from the blood to an inflammatory site in response to chemical or biological stimuli, and may be involved in both acute and chronic inflammation. LTB.sub.4 also appears to be associated with rheumatoid spondylitis and gout. Thus, the 5-lipoxygenase inhibitors of this invention, by inhibiting the production of leukotrienes, may prevent or alleviate the allergic, inflammatory, or hypersensitivity conditions associated with leukotrienes.
Non-steroidal antiinflammatory agents, such as aspirin, indomethacin, ibuprofen, and the like, inhibit prostaglandin biosynthesis by blocking the cyclooxygenase pathway of arachidonic acid metabolism. As a consequence, leukotriene levels may increase as arachidonic acid is metabolized along the 5-lipoxygenase pathway, producing allergic reactions. Administration of 5-lipoxygenase inhibitors of this invention may be effective in reducing undesirable side effects associated with non-steroidal antiinflammatory agents when administered separately or in combination.
See (1) P. Sirois, "Pharmacology of Leukotrienes" in Advances in Lipid Research , 21 , 79-101 (1985); (2) M. K. Bach, "Inhibitors of Leukotriene Synthesis and Action" in The Leukotrienes: Chemistry and Biology , L. W. Chakrin and D. M. Bailey, eds., pp. 163-194 (Orlando: Academic Press, 1984); (3) M. K. Bach, Bioch. pharmacol. , 33 , 515-521 (1984); (4) C. W. Lee et al. , "Human Biology and Immunoreactivity of Leukotrienes" in Advances in Inflammation Research , 6 , 219-225 (1984); (5) P. Sharon and W. F. Stenson, Gastroenterology , 84 , 454-460 (1984); (6) E. L. Becker, Trends Pharmacol. Sci. , 4 , 223-225 (1983); (7) Editorial, "Leukotrienes and Other Lipoxygenase Products in the Pathenogenesis and Therapy of Psoriasis and Dermatoses" in Arch. Dermatol. , 119 , 541-547 (1983); (8) B. Samuelsson, Science , 220 , 568-575 (1983); (9) R. A. Lewis et al. , Int. J. Immunopharmac. , 4 , 85-90 (1982); (10) M. W. Musch et al. , Science , 217 , 1255-1256 (1982).
Unlike earlier therapeutic agents that treat symptoms rather than causes, the compounds of this invention and the pharmaceutical compositions thereof block the formation of causative mediators of allergic and inflammatory conditions and are therefore useful in the treatment of allergic reactions, inflammation, and other conditions associated with leukotrienes.
(b) Background Information
European Patent Applications EP 0195097 and EP 0142145 disclose compounds of the formula ##STR2## or a salt thereof,
in which Y is a group ##STR3##
where m is an integer of from 1 to 5
n is an integer of from 4 to 12
each of R.sup.1 and R.sup.2, which may be the same or different, represents hydrogen or C.sub.1-6 alkyl
X represents a double or triple bond, and each of
A and B represents hydrogen when X is a double bond, or both A and B are absent when X is a triple bond.
These compound are arachidonic acid analogues which are said to be useful in treating allergic diseases. These compounds differ structurally from the compounds of the present invention since they always have unsaturation in the hydrocarbon chain attached to the phenyl.
Some 2-(4-substituted)phenylmethylene compounds have been used as intermediates in the synthesis of other compounds.
J. MED. CHEM., 15(12):1297-1306 (1972) generically discloses intermediates of the formula ##STR4## wherein R =H, alkyl, cycloalkyl which are used to make indan-1-carboxylic acids of the formula ##STR5##
The indan-1-carboxylic acids are said to have antiinflammatory activity. Intermediates in which R is isopropyl, isobutyl, cyclopentyl, cyclohexyl, and cycloheptyl are specifically disclosed in Table II on page 1296. No biological activity is disclosed for the intermediates.
U.S. Pat. No. 3,925,395 generically discloses intermediates of the formula ##STR6## wherein R.sup.2 is phenyl, unsubstituted or substituted by 1 to 3 of the same or different substituents selected from the group consisting of alkyl, especially lower alkyl, alkoxy, especially lower alkoxy, halogen, nitro. cyano, trifluoromethyl, carbalkoxy, especially carb/lower alkoxy and SO.sub.3 -alkyl, especially lower alkyl. These intermediates are used to make 4-aryl-6-amino-3,4-dihydropyrid-2-one-3,5-dicarboxylic acid esters which are said to be useful as coronary agents and as anti-hypertensive agents. No biological activity is disclosed for the intermediates.
U.S. Pat. No. 3,962,269 generically discloses intermediates of the formula EQU ArCH.dbd.C(CO.sub.2 C.sub.2 H.sub.5).sub.2
wherein Ar is phenyl, halophenyl, hydroxyphenyl, methoxyphenyl, methylphenyl, trifluoromethylphenyl, or 3-pyridyl. Intermediates of the formula ##STR7## wherein R is 2-methyl, 3-methyl, 3-methoxy, 4-methoxy, 2-chloro, 3-chloro, 4-chloro, 2,4-dichloro, 4-fluoro, or 4-.phi.CH.sub.2 O are disclosed (See Table 2 at columns 13 and 14). No biological activity is given for these intermediates. They are used to make 2-substituted-1,3-propanediols which are also intermediates.
U.S. Pat. No. 3,799,936 and its divisional, U.S. Pat. No. 3,932,646 generically disclose intermediates of the formula ##STR8## wherein R is phenyl, unsubstituted or substituted by up to three substituents selected from the group consisting of lower alkyl, lower alkoxy, halogeno, trifluoromethyl, or carbo-(lower alkoxy). These intermediates are used to make unsymmetrical esters of 1,4-dihydropyridine 3,5-dicarboxylates which are cardiovascular agents. No biological activity is disclosed for the intermediates.
U.S. Pat. No. 4,769,375 discloses benzylidene intermediates of the formula ##STR9## in which R.sup.1 is phenyl which may be substituted with C.sub.1 -C.sub.4 -alkyl, F, Cl and NO.sub.2 ; R.sub.2 can be H or --COR.sup.5, wherein R.sup.5 is C.sub.1 -C.sub.4 alkyl or --OR.sup.6, wherein R.sup.6 is C.sub.1 -C.sub.6 alkyl; R.sup.3 can be phenyl or C.sub.1 -C.sub.4 alkyl. These benzilidene derivatives are used to prepare circulation-active 1,4-dihydropyridine derivatives. No biological activity is disclosed for the derivatives. No compounds in which R.sup.1 is C.sub.1 -C.sub.4 -alkylphenyl are exemplified. No p-chlorophenyl or p-nitrophenyl compounds are exemplified.
U.S. Pat. No. 3,946,026 generically discloses dicarbonyl intermediates of the formula ##STR10## wherein R can be phenyl which can be substituted with lower alkyl, halogen or nitro; R.sup.1 can be H, lower alkyl, phenyl, or pyridyl; and R.sup.2 can be lower alkyl. These intermediates are used to make 2-amino-1,4-dihydropyridine derivatives which are said to be useful as antihypertensive agents and coronary vessel dilators. No biological activity is disclosed for the dicarbonyl intermediates.
U.S. Pat. No. 4,755,512 discloses intermediates of the formula ##STR11## wherein R.sup.4 can be cycloalkyl, aryl including phenyl, or hetaryl, which can be substituted with lower alkyl, lower alkoxy, cyano, halogen, hydroxyl, nitro, trifluoromethyl, etc., R.sup.5 can be lower alkyl, R.sup.6 can be lower alkyl, alkanol, alkoxyalkyl, or alkylaminoalkyl. Specifically disclosed are compounds of the formula wherein R.sup.4 =p-nitrophenyl, R.sup.5 =ethyl; R.sup.4 =o-chlorophenyl, R.sup.5 =ethyl; R.sup.4 =m-methylphenyl, R.sup.5 =ethyl; and R.sup.4 =phenyl, R.sup.5 =ethyl (See Table 2 at Columns 15-16). These intermediates are used to make dihydropyridinyldicarboxylate amides and esters incorporating arylpiperazinyl moieties which are said to be useful as calcium and alphaadrenergic blockers and to have antihypertensive, antiischemic, and platelet function inhibiting actions. No biological activity is disclosed for the intermediates.
U.S. Pat. No. 4,414,213 discloses intermediates of the formula ##STR12## wherein R.sup.3 can be phenyl substituted with acetamino, C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy, cyano, halogen, hydroxyl, nitro, etc., and R.sup.4 can be lower alkyl or alkoxyalkyl. Specifically disclosed are compounds in which R.sup.4 is ethyl and R.sup.3 is phenyl, p-nitrophenyl, m-chlorophenyl, and o-chlorophenyl (See Table 2 at Columns 8-9). These intermediates are used to make dihydropyridyl cyclicinidate esters which are said to demonstrate blockage of calcium ion flux and vasodilation activities. No biological activity is disclosed for the intermediates.
Weis, A. L, et al., ISR. J. CHEM., 27(1):105-10 (1986) discloses intermediates of the formula ##STR13## wherein Ar is phenyl and R.sup.2 is methyl or ethyl; Ar is o-nitrophenyl and R.sup.2 is methyl or ethyl; and Ar is m-nitrophenyl or p-nitrophenyl and R.sup.2 is ethyl. The intermediates are used to make 4-aryl-1,4-dihydropyrimidine-5-carboxylate calcium antagonists. No biological activity is disclosed for the intermediates.
U.S. Pat. No. 3,905,987 discloses intermediates of the formula EQU ArCH.dbd.C(CO.sub.2 C.sub.2 H.sub.5).sub.2
wherein Ar can be phenyl, halophenyl, hydroxyphenyl, methoxyphenyl, methylphenyl, trifluoromethylphenyl, or 3-pyridyl (See Table 2 at Columns 14-15). These intermediates are used to make m-dioxane-5-methylamine analgesics. No biological activity is disclosed for the intermediates.
CA 109:128499f discloses benzilideneacetone intermediates of the formula RC.sub.6 H.sub.4 CH:CHCOMe (R=4-NO.sub.2, 4-Cl) used in a condensation reaction with arylamines. No biological activity is disclosed for the benzilideneacetone intermediates.
J. A. Cabello, et al., J. ORG. CHEM., 51(10):1786-90 (1986) discloses regioselective 1,4-hydrogenation of benzilidene ketone intermediates of the formula XC.sub.6 H.sub.4 CH.dbd.CHCOR. Specifically disclosed are compounds in which X,R=Me; X=Me, R=Ph (See Table II on page 1788). No biological activity is given for the benzilidene ketones.
J. A. Ciller, et al., ORG. PREP. PROCED. INT., 18(4):227-36 (1986) discloses intermediates of the formula ##STR14## wherein Ar=p-CH.sub.3 C.sub.6 H.sub.4, p-ClC.sub.6 H.sub.4 ; R.sub.1 =CH.sub.3 or C.sub.6 H.sub.5, R.sub.2 =CH.sub.3 or C.sub.6 H.sub.5 (See Table 1 at page 230).